Current trends in the development of new drugs are focused on the method combinatorial chemistry which allows to simultaneously synthesize tens of thousands of chemical compounds and then screen their biological activities at a time. Currently, the combinatorial chemistry is the most effective method in the discovery process of lead compounds for new drugs or in the discovery process of new drug candidates having high biological activities among derivatives of lead compounds.
Combinatorial chemistry has been rapidly advanced since the solid phase reaction was made possible by the development of Merrifield resin in 1963, while previously chemical reactions were conducted only in the liquid phase. Subsequent development of new solid phase resins by many researchers, for example Wang etc. has spurred further advances in the field of solid phase chemical reactions. In early days solid phase synthesis was concentrated on the synthesis of peptides and oligonucleotides, and then is used as universal and the most effective way to generate libraries of chemical compounds. For the solid phase synthesis, it may be possible to remove solvents and reagents used in excess by a simply filtering the final products as well as to simultaneously synthesize large numbers of molecules and thereby much more rapidly and easily synthesize large numbers of molecules than the conventional liquid phase reactions.
According to the above mentioned advantages of the solid phase reactions, the combinatorial chemistry may allow to rapidly and easily generate libraries of chemical compounds that may vary in their chemical structures, by repeatedly and systematically combining components having various chemical structures and thereby using minimum time and efforts in the synthesis of new compounds.
Solid phase synthesis was firstly used in the synthesis of peptides in the 1960s, and then applied in the synthesis of non-peptides in the 1970s, and finally a group of compounds composed of peptides has been made for the first time in the 1980s, while the development of appropriate synthetic apparatuses suitable for combinatorial chemistry was insufficient. Synthetic technologies suitable for the concept of combinatorial chemistry in the discovery process of new drugs have been started to develop in the 1990s, and subsequently, the necessary synthetic apparatuses have been started to develop.
As above mentioned, the technologies of combinatorial chemistry advance steadily, but the technologies in Korea related to syntheses and apparatuses remains to be developed as it is still new area.
Generally, for a reaction vessel used to construct groups of chemical compounds by solid phase synthesis method, a microtiter well plate having a plurality of wells or a vessel in the form of an injection syringe is used. For an instance, the most recently produced organic synthetic apparatus from FlexChem Corp. has adopted a box having 96 wells as a synthetic vessel and the apparatus was devised that the chemical reactions are conducted within the every respective well. However, it is very difficult to observe the reaction phenomena taking place in each well during reaction, and also practically impossible to confirm the chemical process in each and all of the 96 wells. Further, the reaction vessels where resin is laminated in the vertical direction demand a considerable time to set the initial reaction apparatus, and it is hard to secure the airtightness of the filter during the reaction.
For another example, the synthetic apparatus produced by Advanced ChemTech Corp. has also adopted vertical style for the reaction vessels and so it has similar problems as above FlexChem Corp's.
Further, automatic or semiautomatic synthetic apparatuses produced by Chiron Corp., Bodhan Automation, Inc., and Ontogen Corp. has also of vertical styles, and are inconvenient in that each requires an installment of specific gaskets. Moreover, in such reaction devices comprising many reaction vessels as the above it is difficult to oversee each and all the phenomena occurring during the reaction in all those vessels, and also because it is improper to use the very same reaction conditions for all syntheses of new substances at all times it follows that all organic synthesis conditions do not always fit to these automatic apparatuses, posing a serious problem Ralph A. Rivero, Michael N. Greco, and Bruce E. Maryanoff: Equipment for the High-throughput Organic Synthesis of Chemical Libraries, 1997, A Practical Guide to Combinatorial Chemistry, ACS); it is not only impossible to perform the whole steps of reaction automatically, but such automatic appliances are not commonly used because of it's extremely high price(R. N. Zuckermann et al.: Int. J. Pept. Protein, Res., 40, 497 (1992); R. Frank et al.: Tetrahedron, 44,6031 (1988); Automated Combinatorial Chemistry on Solid Phase, Ontogen Corp.).
To produce groups of chemical compounds by combinatorial chemistry, it is required first to see if a reaction is successful in the liquid phase, and, if it is, next to try a reaction in the solid phase, and, if successful again, then to construct a library of the compounds. The constructed libraries are arbitrarily or selectively, wholly or partially, subjected to a quality control. A number of libraries had been constructed by way of above methods in early days, but nowadays approaches which lead to generate more focused libraries are used in general. But, specialized synthetic companies are still generating tens of thousands or hundreds of thousands of libraries from a same scaffold In these cases, a certain number of lead compounds for a desired target compound may be usually found within several months.
As mentioned above, synthetic apparatuses capable of synthesizing compounds automatically or semiautomatically may well be required when a large numbers of libraries arc to be generated, but also there's a case any special synthetic apparatus is not needed when only scores or hundreds of libraries are to be generated.
As a synthetic reaction vessel to solve the problems of synthetic apparatuses having vertical types of reaction vessels, “a boat type reaction vessel for synthesis of peptide or DNA” has been described in KP issuance No. patent 1997-4691. while this boat shaped vessel, having an inlet on the left side and an outlet on the right, both formed slantwise, has solved part of the problems of vertical types. But it still has got its own defects in that it is by the nature of its construction difficult to fix the reactors in a certain position, and further, it takes too much time in washing each of the plurality of boat shaped reactors which are required in multiplex synthesis such as libraries of chemical compounds by using a vacuum pump. Moreover, it is too much of a task to separate the final product in the each reactor, one by one, after completion of the reaction.